After traumatic brain injury (TBI) the human APOE-?4 (APOE4) gene polymorphism is associated with increased mortality, increased coma time, poor prognosis, and an increased risk of late-onset Alzheimer's disease (AD). The APOE4 gene is found in 27% of the US population, and as such affects an estimated 459,000 TBI cases each year. It is not known how APOE4 genotype negatively impacts outcome after TBI, or if genotype-specific treatments are required to improve prognosis. TBI causes the accumulation and deposition of a neurotoxic peptide called amyloid-? (A?). Approximately 30% of all fatal TBI cases present with A? plaques, however the deposition of A? is dependent on the APOE genotype of the patient. Only 10% of non-APOE4 brains have A? plaques after injury, while 35% of heterozygous APOE4 brains, and 100% of homozygous APOE4 brains, develop A? plaques. The APOE gene encodes for the apolipoprotein E (apoE) protein, which was recently shown to facilitate the enzymatic degradation of A?. These data suggest that individuals carrying the APOE4 genotype are unable to clear the excess A? that is produced as a result of TBI. Accumulation of excess A? is known to cause neuronal apoptosis and trigger neuroinflammation. We have recently shown that preventing A? production, or enhancing A? clearance, can ameliorate secondary injury and prevent cognitive and motor deficits caused by experimental TBI in mice. Here we will study the role of apoE isoforms in A? clearance after TBI. We are testing the hypothesis that apoE is instrumental in A? degradation after TBI, but the apoE4 isoform is dysfunctional at this process. We believe that the accumulation of A? in APOE4 mice leads to increased cell death and poorer functional and cognitive outcome after injury. We will test this hypothesis in our Specific Aims: Aim 1) Determine the role of apoE in A? clearance after TBI Aim 2) Determine the effect of APOE genotype on A? clearance after TBI Aim 3) Test if the poorer prognosis after TBI in APOE4 carriers is due to prolonged A? accumulation These data will allow us to determine the mechanism by which A? accumulates aggressively in APOE4 patients after TBI, and the functional consequences of that A? accumulation.

Public Health Relevance

After traumatic brain injury (TBI) the human APOE-?4 (APOE4) gene polymorphism is associated with increased mortality, increased coma time, poor prognosis, and an increased risk of late-onset Alzheimer's disease (AD). The APOE4 gene is found in 27% of the US population, and as such affects an estimated 459,000 TBI cases each year. It is not known how APOE4 genotype negatively impacts outcome after TBI, or if genotype-specific treatments are required to improve prognosis. This R01 proposal proposes that impaired clearance of the neurotoxic A? peptide after TBI is responsible for these detrimental effects, and tests pharmacological treatments to reverse these deficits.